Vemurafenib + Metformin for Melanoma

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Louisville

Disqualifiers: Prior Vemurafenib, Metformin hypersensitivity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

55 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety of using Vemurafenib, a targeted therapy, in combination with Metformin for treating melanoma, a type of skin cancer. Researchers aim to determine if this combination can improve outcomes, particularly for patients with advanced stages of the disease. Melanoma patients with the BRAFV600E genetic marker who have not previously received Vemurafenib may be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Vemurafenib, when used alone, is effective in about 50% of patients with certain types of melanoma. In a study with 75 patients, it achieved a 46% success rate, indicating its potential effectiveness for some individuals with this cancer.

Early research suggests that combining Vemurafenib with Metformin can help stop melanoma cells from growing in lab tests, offering a hopeful sign for treating the disease.

Regarding safety, the FDA has already approved Vemurafenib alone for certain melanoma cases, deeming it reasonably safe at specific doses. Metformin, a common diabetes drug, is added at safe levels to minimize side effects. However, since this study is in its early stages, researchers continue to closely monitor how well participants tolerate the combination and what side effects might occur.

In summary, while there is hope that this drug combination will be effective against melanoma, the current trial is crucial to confirm its safety for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for melanoma, which often include surgery, radiation, and chemotherapy, the combination of Vemurafenib and Metformin offers a fresh approach by targeting the BRAF mutation in melanoma cells. Vemurafenib is a BRAF inhibitor that directly attacks cancer cells with this specific mutation, potentially making it more effective for patients with this genetic profile. Meanwhile, Metformin, commonly known for its use in diabetes, may enhance the effectiveness of Vemurafenib by disrupting cancer cell metabolism. Researchers are excited about this combination because it not only targets the cancer cells more precisely but also leverages Metformin's potential anti-cancer properties, which could lead to improved outcomes for patients.

What evidence suggests that the combination of Vemurafenib and Metformin could be effective for melanoma?

Research shows that combining vemurafenib and metformin might help treat melanoma, a type of skin cancer. In this trial, participants will receive both vemurafenib and metformin. Studies have shown that this combination more effectively stops the growth of melanoma cells with the BRAFV600E mutation. Previously, patients with this mutation who took vemurafenib alone had a 46% response rate, with many experiencing cancer shrinkage or halted growth. Metformin, a common diabetes medication, also slows melanoma cell growth in lab studies. These findings suggest that using both treatments together could improve outcomes for melanoma patients. ^{4 6 7 8 9}

Who Is on the Research Team?

Jason Chesney, MD

Principal Investigator

James Graham Brown Cancer Center-U of Louisville

Are You a Good Fit for This Trial?

This trial is for adults with BRAFV600E melanoma (Stage IIIC or IV) who can perform daily activities (ECOG PS 0-2) and have a life expectancy of at least 3 months. Participants must be able to use contraception, not be pregnant, and have adequate organ function. They cannot have had prior Vemurafenib treatment or known Metformin hypersensitivity.

Inclusion Criteria

My melanoma is BRAFV600E positive and is at stage IIIC or IV.

My blood, kidney, and liver tests meet the required levels.

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

I do not have any uncontrolled infections or conditions that could affect the study.

I have not had radiotherapy for non-brain issues in the last 2 weeks or I have recovered from its side effects.

You are allergic to metformin or any of the ingredients in it.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Evaluation of the safety of Vemurafenib in combination with Metformin in patients with unresectable Stage IIIC and Stage IV melanoma

Approximately 6 months

Regular monitoring visits

Phase II Treatment

Evaluation of the clinical activity of the combined Vemurafenib/Metformin regimen

28-day cycles until progression or unacceptable toxicity

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Every 12 weeks (+/- 7 days) after last drug dose

What Are the Treatments Tested in This Trial?

Interventions

• Metformin
• Vemurafenib

Trial Overview The study tests the safety and effectiveness of combining Vemurafenib with Metformin in treating melanoma. It aims to see if this combination improves response rates and survival with little toxicity based on earlier studies.

How Is the Trial Designed?

Group I: Vemurafenib and Metformin Experimental Treatment 2 Interventions

Vemurafenib is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Zelboraf for:

• Unresectable or metastatic melanoma with BRAF V600E mutation
• Erdheim-Chester Disease (ECD) with BRAF V600 mutation

Approved in European Union as Zelboraf for:

• Adults with BRAF V600E mutation positive unresectable or metastatic melanoma

Approved in Canada as Zelboraf for:

• Unresectable or metastatic melanoma with BRAF V600E mutation

Who Is Running the Clinical Trial?

University of Louisville

Lead Sponsor

Trials

353

Recruited

76,400+

James Graham Brown Cancer Center

Collaborator

Trials

44

Recruited

9,200+

Published Research Related to This Trial

Vemurafenib significantly improves overall and progression-free survival in patients with advanced melanoma harboring the BRAF V600E mutation, showing a 63% reduction in the risk of death compared to dacarbazine and a 74% reduction in the risk of death or disease progression.

The drug demonstrated a high objective response rate of 48% in patients treated with vemurafenib, compared to only 5% in those receiving dacarbazine, although it is associated with unique side effects, including the development of secondary skin tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vemurafenib (Zelboraf) in the therapy of melanoma]. Liszkay, G.[2018]

Vemurafenib (Zelboraf) is an FDA-approved medication specifically for treating unresectable or metastatic melanoma in patients with the BRAF(V600E) mutation.

This drug works by inhibiting BRAF kinase, which is a key player in the growth and spread of melanoma cells with this specific mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib. Flaherty, KT., Yasothan, U., Kirkpatrick, P.[2021]

Vemurafenib is the first selective BRAF inhibitor approved for treating advanced melanoma with the BRAF V600 mutation, demonstrating strong efficacy and a favorable safety profile.

The article reviews various studies comparing vemurafenib's effectiveness and toxicity with other treatments like dabrafenib and ipilimumab, highlighting its potential role in future melanoma therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib for the treatment of BRAF mutant metastatic melanoma. Martin-Liberal, J., Larkin, J.[2022]

A new liquid chromatography-tandem mass spectrometry method was developed to accurately quantify vemurafenib levels in human plasma, demonstrating a lower limit of quantification of 0.1 mcg/mL and a linear range from 1.0 to 100.0 mcg/mL.

Vemurafenib showed stability in human plasma for up to one month at various temperatures, which is important for ensuring reliable pharmacokinetic studies in patients with advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and validation of a rapid and simple LC-MS/MS method for quantification of vemurafenib in human plasma: application to a human pharmacokinetic study. Bihan, K., Sauzay, C., Goldwirt, L., et al.[2019]

In a phase 3 trial involving 675 patients with metastatic melanoma and the BRAF V600E mutation, vemurafenib significantly improved overall survival rates (84% at 6 months) compared to dacarbazine (64%).

Vemurafenib also demonstrated a 63% reduction in the risk of death and a 74% reduction in the risk of disease progression compared to dacarbazine, although it was associated with common adverse effects that led to dose modifications in 38% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival with vemurafenib in melanoma with BRAF V600E mutation. Chapman, PB., Hauschild, A., Robert, C., et al.[2022]

In a safety study involving 75 patients with BRAFV600 mutation-positive metastatic melanoma, vemurafenib demonstrated an objective response rate of 46%, with a median progression-free survival of 7.4 months, indicating its efficacy in treating this aggressive cancer.

The safety profile was consistent with previous studies, with 97.3% of patients experiencing adverse events, primarily skin-related issues, and nearly half reporting severe toxicity (grade 3-5), highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial. Rutkowski, P., Kozak, K., Mackiewicz, J., et al.[2020]

The combination of metformin with trametinib and paclitaxel demonstrated varying effects on melanoma cell growth, showing synergistic effects in some cell lines while being antagonistic in others, indicating that the effectiveness of this combination may depend on the specific cellular context.

Metformin appears to enhance the efficacy of trametinib and paclitaxel by suppressing factors involved in epithelial-mesenchymal transition (EMT) and reducing melanoma cell motility, suggesting its potential as an adjuvant treatment to combat melanoma progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Metformin in Combination With Trametinib and Paclitaxel on Cell Survival and Metastasis in Melanoma Cells. Lee, Y., Park, D.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3152784/

Combination therapy with vemurafenib (PLX4032/RG7204 ... In our studies, the combination of vemurafenib and metformin synergistically inhibited proliferation in a subset of human melanoma cell lines and induced cell ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/21609436/

Combination therapy with vemurafenib (PLX4032/RG7204 ... The combination of vemurafenib and metformin tended to have stronger anti-proliferative effects on BRAFV600E mutant cell lines.

3. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/71053

A Phase I/II Trial of Vemurafenib and Metformin to Melanoma ... The main purpose of this study is to evaluate the safety of Vemurafenib in combination with Metformin in melanoma patients. The phase II part of the study ...

4. withpower.com withpower.com/trial/vemurafenib-metformin-for-melanoma-7e4e6

Vemurafenib + Metformin for Melanoma In a safety study involving 75 patients with BRAFV600 mutation-positive metastatic melanoma, vemurafenib demonstrated an objective response rate of 46%, with a ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01840007

Pilot Study Evaluating the Efficacy and Safety of Metformin ... In the case of melanoma, a study published recently has showed that metformin inhibits proliferation of melanoma cells in vitro and we confirmed for our part ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01638676

NCT01638676 | A Phase I/II Trial of Vemurafenib and ... The main purpose of this study is to evaluate the safety of Vemurafenib in combination with Metformin in melanoma patients. The phase II part of the study will ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4064951/

Vemurafenib: an evidence-based review of its clinical utility in ... Vemurafenib induced responses in ~50% of patients with metastatic BRAF-mutant melanoma and demonstrated improved overall survival in a randomized Phase III ...

8. translational-medicine.biomedcentral.com translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-9-76

Combination therapy with vemurafenib (PLX4032/RG7204 ... In our studies, the combination of vemurafenib and metformin synergistically inhibited proliferation in a subset of human melanoma cell lines ...

9. smartpatients.com smartpatients.com/trials/NCT01638676

A Phase I/II Trial of Vemurafenib and Metformin to ... The main purpose of this study is to evaluate the safety of Vemurafenib in combination with Metformin in melanoma patients. The phase II part of the study ...